The present invention relates to methods and devices for treating a patient at risk of loss of cardiac function by cardiac ischemia.
The following references are cited in this application, either as references pertinent to the Background of the Invention, or to methods or materials described in the Detailed Description of the Invention.
Heart disorders are a common cause of death in developed countries. They also impair the quality of life of millions of people and restrict activity by causing pain, breathlessness, fatigue, fainting spells and anxiety. The major cause of heart disease in developed countries is impaired or inadequate blood supply. The coronary arteries may become narrowed due to arteriosclerosis and part of the heart muscle is deprived of oxygen and other nutrients. The resulting ischemia or blockage can lead to angina pectoris, a pain in the chest, arms or jaw due to lack of oxygen to the heart""s myocardium, infarction or tissue necrosis in myocardial tissue. Alternatively, and particularly with age, the extent of vascularization of the heart may diminish, leaving the heart undersupplied with oxygen even in the absence of significant arteriosclerosis.
Coronary-artery blockage can be relieved in a number of ways. Drug therapy, including nitrates, beta-blockers, and peripheral vasodilator drugs (to dilate the arteries) or thrombolytic drugs (to dissolve clots) can be very effective. If drug treatment fails, transluminal angioplasty is often indicatedxe2x80x94the narrowed part of the artery, clogged with atherosclerotic plaque or other deposits, can be stretched apart by passing a balloon to the site and gently inflating it a certain degree. In the event drug therapy is ineffective or angioplasty is too risky (introduction of a balloon in an occluded artery can cause portions of the arteriosclerotic material to become dislodged which may cause a total blockage at a point downstream of the subject occlusion, thereby requiring emergency procedures), the procedure known as coronary artery bypass grafting (CABG) is the most common and successful major heart operation performed, with over 500,000 procedures done annually in America alone. A length of vein is removed from another part of the body. The section of vein is first sewn to the aorta and then sewn onto a coronary artery at a place such that oxygenated blood can flow directly into the heart. CABG typically is performed in an open chest surgical procedure, although recent advances suggest minimally invasive surgery (MIS) techniques may also be used.
Another method of improving myocardial blood supply is called transmyocardial revascularization (TMR), the creation of channels from the epicardial to the endocardial portions of the heart. Initially, the procedure used needles to perform xe2x80x9cmyocardial acupuncture,xe2x80x9d and has been experimented with at least as early as the 1930s and used clinically since the 1960s, see Deckelbaum. L. I., Cardiovascular Applications of Laser Technology, Lasers in Surgery and Medicine 15:315-341 (1994). This procedure has been likened to transforming the human heart into one resembling that of a reptile. In the reptile heart, perfusion occurs via communicating channels between the left ventricle and the coronary arteries. Frazier, O. H., Myocardial Revascularization with Laserxe2x80x94Preliminary Findings, Circulation, 1995; 92 [suppl II:II-58-II-65]. There is evidence of these communicating channels in the developing human embryo. In the human heart, myocardial microanatomy involves the presence of myocardial sinusoids. These sinusoidal communications vary in size and structure, but represent a network of direct arterial-luminal, arterial-arterial, arterial-venous, and venous-luminal connections. The needle technique was not continued because the channels did not remain open, replaced by the use of laser energy to accomplish TMR.
Drug therapies with angiogenic growth factors may expedite and/or augment collateral artery development. To accomplish these needs, drug transfer devices for delivering precise amounts of these drugs can enhance this healing process. Surgeons who deal with minimally invasive surgical techniques, and interventional cardiologists who deal with percutaneous approaches, need devices for drug delivery procedures. The drugs used in modern medical technology are often quite expensive, potentially mixing and/or handling sensitive, and it is a new challenge to make these drugs or other compounds readily available for precise, predetermined delivery during these advanced or other procedures.
The invention includes, in one aspect, a method of treating a patient at risk of loss of cardiac function by cardiac ischemia. The method is practiced by first imaging the patient""s heart, or a portion thereof, to identify (i) an underperfused region of cardiac muscle, (ii) a source of oxygenated blood that is proximate a boundary of the underperfused region, and (iii) a target area that includes the underperfused region boundary and a tissue expanse lying between the oxygenated blood supply and the boundary. A stimulus effective to stimulate angiogenesis in myocardial tissue and form a capillary network from the source of oxygenated blood in the direction of the underperfused region is introduced at each of a plurality of sites throughout the target area. The demand for oxygen at the underperfused region is then sustained for a period sufficient to convert the capillary network into an arteriole network.
The underperfused region is an at risk region of cardiac muscle which is insufficiently perfused to handle heightened activity or is likely to be near term at risk of underperfusion due to the progression of nearby disease and cannot be treated by the full restoration of normal coronary flow.
Usually, patients will enter this treatment regiment by appearing for intermittent angina (intermittent identifies that demand for arterial growth and arterial maturation is not reliably turned on) through drug or exercise stress testing where cardiac reserve appears less than optimal or when a routine treatment such as bypass, angioplasty or stents is unable to restore normalized blood flow, and in the judgment of the cardiologist or surgeon is at risk due to lack of reserve capacity. The imaging step to identify the area at risk and nearby source of oxygenated blood (target) may be carried out by monitoring blood flow in the heart by myocardial perfusion imaging by single-photon emission computed tomography (SPECT), positron-emission tomography (PET), echo-planar imaging, MRI, or angiogram.
The source of oxygenated blood in the method may be one in which arteries less than about 1 mm branch into surrounding arterioles, and in which the arterioles with inner-lumen diameters between about 50-200 microns are plentiful, and the sites are spaced from one another at spacing of between 0.5 to 1 cm. Alternatively, or in addition, the underperfused region may be a myocardial region of either of the patient""s ventricles, and the source of oxygenated blood, the interior of the underperfused heart ventricle region. Here the target area includes the region of ventricle endocardium underlying the underperfused region.
The stimulus introduced at each of the target-area sites may be a growth factor, such as basic or acidic fibroblast growth factor-1 (FGF-2, FGF-1), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), or combinations of two or more of these growth factors. The growth factor may be introduced in the form of a recombinant protein carried in a pharmaceutically acceptable medium, a vector containing the coding sequence for the growth factor and a control region effective to promote transcription of the coding region in patient myocardial cells, and/or in the form of a myocardial or cardiac myoblast cells which have been transformed with a gene encoding the growth factor. The manner of introducing the growth factor may be by (i) injecting the protein, vector of cells directly into myocardial tissue at each site, (ii) drawing the protein or vector into myocardial tissue at each site by iontophoresis from a reservoir placed against the site, (iii) forming a channel in the myocardium at each site, and placing the protein, vector or cells into the channel, or (iv) bombarding each site with a biolistic particle containing or coated with the protein, vector or cells. For example, an angiogenic stimulus would be used without adjunctive biological triggering when the target area is predetermined at the patient evaluation and diagnosis stage to have sufficient preexisting tissue demand for oxygen in the form of significant angina (Canadian Heart Class 4) or when the physician has predetermined that the patient can exercise post treatment to provide dependable tissue demand for arteriole growth beyond the pre-existing patient reserve capacity.
In another general embodiment, the stimulus, or biologic trigger, introduced into the target-area sites is an injury produced by a mechanical, laser, chemical, thermal, or ultrasonic stimulus. This type of stimulus may be additive to the effect of a drug stimulus by turning on the local naturally-occurring angiogenic processes. In the process of adding a biologic trigger a new immediate tissue demand for oxygen is added which can be effectively used where Class 4 Angina is not available and exercise cannot be used due to related concerns. For example, the injury may be produced by a mechanical cutting device effective to produce an annulus of injury about a core of healthy cells. Alternatively, the injury may be produced by introducing into each of the sites, a wire device having a barbed segment, where the method further includes periodically moving the wire devices relative to the heart, to produce a prolonged angiogenic stimulus at the site. In another example the stimulus may include a mechanical injury produced by forming, at selected target sites in the target area, elongate channels in the endocardium of the ventricle to stimulate angiogenic growth from the ventricle to neighboring target regions as described above. The depth and width of the endocardial channels, combined with the blood turbulence produced within the ventricle, is such as to minimize accumulation of blood clot material in the channels. The channels have preferred width and depth dimensions between 1-5 mm. This embodiment of the method may further include imaging the heart to identify (i) as a second source of oxygenated blood, coronary arterioles in the epicardial region of the ventricle overlying the underperfused heart-ventricle region, (ii) as a second target area, the area between the second source of oxygenated blood supply and the underperfused region, and the adjacent boundary of the underperfused region. There is then introduced into the second target area, at selected sites therein, a stimulus effective to stimulate angiogenesis in the target area. Sustained demand can also be created with chemical methods such as acidic injections, with implants that elicit a foreign body response, and with viral carriers which might be used to facilitate angiogenic gene transfer.
The sustained demand may be by requiring the patient to adhere to an exercise regimen, or by producing a recurrent or slow-healing injury at or near the target-area sites. For example, sustaining the demand may include the additional steps, after initially inducing capillary blush, of equipping the patient with an exercise monitor that indicates the level and amount of heart exercise the patient achieves, and requiring the patient to achieve an amount and level of heart exercise effective to stimulate the conversion of capillary blush produced by the introducing step to arterioles in the target area. The exercise regimen is carried out over a period of at least weeks 4-15 following the introduction of angiogenic stimuli.